Genetic Basis of Developmental Disorders

Question 1

What are developmental disorders?

Answer 1

-Genesis during embryogenesis or early brain development
=Intellectual disability
=global developmental delay
=malformations
=infantile seizures
=motor disorders
=sensory impairments

Question 2

Describe the project DDD

Answer 2

-Deciphering Developmental Disorders
=Objectives to research genetics of DD, translate to NHS diagnostics, tri-based whole exome analysis (both parents and child)
=Blood and saliva DNA
=Phenotype HPO, growth, development, images

Question 3

What is a de novo mutation?

Answer 3

-Monogenetic= one copy of gene affected
=Not present in either parent
=During biological processes
=Increases with paternal and maternal age
(1 in 377 if 20, 1 in 168 if 45)

Question 4

What types of links can be made between genes and disease entity?

Answer 4

• Allelic requirement
• Functional mechanism (activating/ loss of function)
• Confidence of association (confirmed/ probable/ possible)
• Link to evidence

Question 5

What is the commonest type of genes that mutate for DD?

Answer 5

• Chromatin-associated proteins= general effect of gene expression on many genes
• Complexes, like chromatin-remodelling complexes
• Modularity

Question 6

What are the causes of developmental disorders?

Answer 6

-40% diagnostic rate
=78% de novo
=12% recessive
=10% inherited (het/hemi)
-Plus 4% uncertain

Question 7

What is the cause in the 59% exome-negative probands?

Answer 7

• False negatives
• Cis-regulatory mutations
• Mosaicism
• Non-coding genes
• 5’ or 3’ UTR variants
• Balanced chromosomal rearrangements
• Oligogenic
• Non-genetic

Question 8

How can we find cis-regulation mutations?

Answer 8

• Look for evidence there is a signal there if cannot identify exact mutation
• Enhancers sequenced
• Same element as a target of de novo mutation
• Number of de novo mutations observed vs number expected by chance
• Enhancers during early brain developed, enhancers conserved through evolution/ recurrently hit